Use of essential fatty acids for the preparation of a drug for the treatment of infantile seborrheic eczema

ABSTRACT

The use of essential fatty acids having 18-20 carbon atoms for producing a pharmaceutical preparation for the treatment of infantile seborrhoeic eczema or asteatotic eczema.

The present invention relates to the use of essential fatty acids having18-20 carbon atoms in the preparation of a drug for the treatment ofinfantile seborrhoeic eczema and asteatotic eczema.

Essential fatty acids are long-chained unsaturated fatty acids acidswhich cannot be synthetized in the body but must be provided via food.

Linoleic acid, which is the essential fatty acid having the shortestchain, metabolizes by elongating and desaturating via gammalinolenicacid and dihomogammalinolenic acid to arachidonic acid, which is aprecursor for prostaglandin E₂, PGE₂.

It is known that a deficiency of PGE₂, which inter alia comprises atransport ligand for zinc in the mucous membrane of the intestines,brings about reduced zinc absorption in humans and that the enzymedelta-6-desaturas, D-6-D, is zinc dependent.

By testing on animals it has been shown that desaturating of linoleicacid to gammalinolenic acid mediates via D-6-D.

Linoleic acid (ω-6-C18:2) hence desaturates via D-6-D to gammalinolenicacid (ω-6-C18:3), which elongates to dihomogammalinolenic acid(ω-6-C20:3), which in its turn via the enzyme D-5-D, desaturates toarachidonic acid (ω6-C20:4).

Since the essential fatty acids, which via food are provided to humans,consist almost entirely of linoleic acid, the amount of the essentialfatty acids gammalinolenic acid, dihomogammalinolenic acid andarachidonic acid metabolized in the body will successively decrease ifthe activity of D-6-D is reduced or stopped.

In studies of experiments with animals it has been shown thatD-6-D-activity in rat fetuses is very low. The state in humans isunknown.

There are no reported cases of naturally occurring deficiency ofessential fatty acids in humans.

The function and importance of linoleic acid in the skin is that it isincorporated in the membranes and enzymes, it is important for thebarrier functions of the skin (permeability and absorption) and thatlack of linoleic acid results in a defective shield in the horny layer.

The function and importance of arachidonic acid is that it isincorporated in the phospholipides of the skin (lecithin,phosphatidylethanolamine) and it is a precursor for prostaglandins whichregulate the balance of epidermis and mediate inflammation. Lack ofarachidonic acid in the skin affects the regulation of the horny layerand of inflammatory conditions.

Deficiency of essential fatty acids, however, has been described as apost-operative effect in surgery and as a secondary effect ofmanipulation of the diet. The manifestation of the skin in saiddeficiency has then been that of dry, scaly, leathery-like inflamed skinconditions. Oozing, secondarily-infected lesions mainly in body foldsare usually apparent. Furthermore, an increased transepidermal waterloss has been observed.

In studies regarding skin changes due to zinc deficiency in infants twoclinically distinctive types have been observed:

1) The classic zinc deficiency dermatitis with low zinc value in serum.These infants all had a low zinc intake due to a low zinc content intheir mothers breastmilk. The skin changes were primarily localised inthe diaper region, the face, the back of the hands and the feet withquite distinctively demarcated plaques, in some places heavily scaling,almost of psoriasis form type. These children responded promtly and wellto applied zinc substitute.

2) The symptoms often first appeared in 3-6 weeks old infants startingin the diaper region, where skin changes were more confluent.Furthermore, round to oval reddish, somewhat thickened, lightly scalingpatches could be seen. The scalp was covered by a thick, yellow-brown,somewhat greasy desquamation. In body folds, armpits and behind theears, red, oozing lesions could be seen, often secondarily infected.

Type 2) on analysis of essential fatty acids in serum has been shown tohave a pattern that corresponds to a defectively functioning D-6-D.These children had a slightly decreased zinc value in serum, which isthought to be a side effect due to reduced PGE₂ -production. Infantswith skin lesions according to Type 2 recovered spontaneously when theyreached the age of 4-7 months. The fatty acid pattern and zinc valuealso normalise at the same point of time. This is believed to dependupon a maturing of the function of D-6-D in said infants which for someunknown reason had been delayed. Prematurely born babies seem moreinclined to show this condition.

Skin diseases and symptoms in the aged, especially during winter, showdry, scaling, crackled skin with nummular, inflammatory lesions.Conditions of this type are described under several diagnoses such as:asteatotic eczema, eczema craquele, xerotic eczema, senile eczema,eczema hiemalis and winter-itch. In the present context only thedescription asteatotic eczema is used. This condition is probablyrelated to a decreased activity of the enzyme D-6-D due to ageing.

Asteatotic eczema has previously been treated with steroid preparationsand emollients or by reduced water contact. In cases of a higher degreeof inflammation the treatment has not been apparently successful.

As a result of the research work carried out regarding zinc deficiencyin infants it has now been found that the lesions which appeared,depending upon a too low D-6-D-activity, correspond with those seen ininfantile seborrhoeic eczema. It has even been found that the conditioncan be successfully treated by topical application of a preparationcontaining 0.1-100% by weight of gammalinolenic acid,dihomogammalinolenic acid or arachidonic acid. Intravenous or oraladministration is also judged to be effective. In previous treatment ofinfantile seborrhoeic eczema, steroid preparations, diiodoquin,antibacterial agents, antibiotics and emollients in general have beenused. No apparent improvement has, however, been achieved by thistreatment.

The active substance is locally supplied as pure fatty acids or includedin vegetable oils or oils obtained by other means or in the form ofointments, creams or pastes mixed with the usual bases for ointments andcreams used in pharmaceutical techniques, such as wool oil, vaseline,animal fats and vegetable fats, waxes, paraffin, cetyl alcohol andstearyl alcohol, silicones and glycerine.

When the active substance comprises gammalinolenic acid it is generallyobtained in the form of vegetable oils such as, for example, eveningprimrose oil, containing about 10% gammalinolenic acid or borage oil,i.e. the oil from borago officinalis containing about 24% gammalinolenicacid, or by other means.

Dihomogammalinolenic acid can be obtained by chemically processinglinoleic acid or by extraction from certain vegetable oils andarachidonic acid can be obtained by chemically processingdihomogammalinolenic acid.

In addition to the active substance and the usual formulation substancesand preservatives, emulsifying agents, agents for expanding viscosity,dispersing agents, solidifyers and antioxidants, zinc can even beincluded in an amount of 1-30% by weight of the total product andprostaglandin, PGE₁ or PGE₂ in an amount of 0.1-10% by weight of thetotal product.

Furthermore, if so desired and so required, additional active substancessuch as antibacterial agents, antibiotics, steroid preparations andantimycotic agents can be included in an amount not exceeding 10% byweight of the total product.

Preferred amounts of the active fatty acid are 0.5-50% by weight,preferably 1-20% by weight and most preferably 5-10% by weight of thetotal composition.

Optional zinc is added preferably in an amount of 15-25% by weight ofthe total composition and most preferably about 20% by weight.

The preferred amounts of prostaglandin are 0.1-2% by weight of the totalproduction and most preferably 1% by weight and the preferred amounts ofadditional active substances are about 5% by weight.

Oral administration, mentioned above, is supplied in the form ofcapsules or tablets with a coating consisting of gelatine or starch.

The active substance in the capsule or the tablet can be supplied as oilcontaining the active fatty acid in an amount of 100-600 mg, whichcorresponds to an amount of active substance of 10-120 mg per capsule,depending upon the oil used.

Previous treatment with essential fatty acids are described by Shepardand Linn in The Drug and Cosmetic Industry, vol. 38, p. 629 (1936), inwhich rats having a deficiency of essential fatty acids were treatedlocally with vitamin F (prostaglandins) with positive results.

Hartop and Prottey describe in Brit. Journal of Dermatology, vol. 95, p.255 (1976) topical treatment with fatty acid triglycerides givingpositive results on rats with deficiency of essential fatty acids, andZiboh and Hsia describe in an article in J. Lipid Research, vol. 13, p.458 (1972) topical treatment of rats having a deficiency of essentialfatty acids with prostaglandin E₂, in which the scaling which occurredhealed.

On humans with a deficiency of essential fatty acids due to parenteralnutrition topical treatment consisting of safflower oil (Carthammustinctorius) containing approx. 60-70% linoleic acid but nogammalinolenic acid, is described by Skolnik, Eaglstein and Ziboh inArchives of Dermatology, vol. 113, p. 939 (1977).

In Pediatrics, vol. 58, p. 650 (1976) Friedman describes the treatmentof two children, having total parenteral nutrition, with sunflower oilcontaining approx. 60% linoleic acid and 0% gammalinolenic acid. In theJournal of Invest. Derm., vol. 64, p. 228 (1975) Prottey et al describetreatment with sunflower oil to three patients with chronicmalabsorption and deficiency of essential fatty acids giving positiveresults and Press describes in the Lancet, vol. 1. p. 597 (1974) there-establishment of the fatty acids balance in three patients who hadundergone surgery on the intestines.

In an article in Prostaglandins, Leukotrienes and Medicine, vol. 9, p.615-628 from 1982, Manku and Horrobin describe the treatment of 50patients having atopic eczema by oral administration of evening primroseoil, containing approx. 60% linoleic acid and approx. 10% gammalinolenicacid. The treatment gave a somewhat improved result.

In 1986 Galland in Journal of the American Coll. of Nutr., vol. 5, p.213, describes the treatment of a number of atopics with eveningprimrose oil which gave doubtful result.

There is, however, no previous information at all that gammalinolenicacid, dihomogammalinolenic acid and/or arachidonic acid in a superiormanner hitherto unknown, help the deficiency symptoms which appear indefective D-6-D activity, especially in infants.

The invention is further illustrated by the following non-limitingexamples and test reports.

EXAMPLE 1

A preparation for intravenous injection was prepared in a conventionalmanner by mixing 10 mg prostaglandin E₂ and 100 ml sterile sodiumchloride solution of 0.9%.

EXAMPLE 2

A capsule for oral administration was prepared by filling soft gelatinecapsules of a suitable size and form with 400 mg evening primrose oil oralternatively 200 mg borage oil and then sealing.

EXAMPLE 3

Creams and ointment bases were prepared in a conventional manner, forexample, by mixing:

    ______________________________________                                        Liquid cream                                                                             Propylene glycol   5%                                                         Carbopol ® 940   0.25%                                                    Borage              12.5%                                                     Bleached bees-wax  3%                                                         Spermaceti         3%                                                         Lanette ® SX   1%                                                         Stearin              0.2%                                                     Glycerylmonostearate                                                                               0.3%                                                     Preservative       qs                                                         Triethanolamine      0.5%                                                     Water              ad 100                                          Normal cream                                                                             Emulgade CBN       20%                                                        Borage             8%                                                         Lanette ® O    2%                                                         Propylene glycol   2%                                                         Preservative       qs                                                         Water              ad 100                                          Normal Cream                                                                             Glycerylmonostearate                                                                             12%                                                        Lanette ® O    1%                                                         Cutina ® E 24  3%                                                         Eumulgin B2        1%                                                         Cetiol ® SB 45/shea-butter                                                                   10%                                                        Borage             10%                                                        Eutanol ® G    10%                                                        Propylene glycol   5%                                                         Preservative       qs                                                         Water              ad 100                                          Lotion     Cutina ® CBS   8%                                                         Cutina ® E 24  2%                                                         Eumulgin B2        2%                                                         Cetiol ® SB 45/shea butter                                                                   4%                                                         Eutanol ® G    3%                                                         Borage             4%                                                         Glycerine 1.23     3%                                                         Preservative       qs                                                         Water              ad 100                                          Normal cream                                                                             Gelot 64 (glyceryl-                                                                              15%                                                        stearate PEG-75 stearate                                                      (CTFA))                                                                       Labrafil M 2130    2%                                                         Borage             6%                                                         Preservative       qs                                                         Water              ad 100                                          Normal cream                                                                             Tefose 63 (PEG-6-23                                                                              15%                                                        stearate glycolstearate                                                       (CTFA))                                                                       Labrafil M 1944    3%                                                         Borage             8%                                                         Preservative       qs                                                         Water              ad 100                                          ______________________________________                                    

Carbopol--polymer of acrylic acid cross-linked with allylsaccharose

Lanette O--cetearyl alcohol

Lanette SX--sodiumalkylsulphate, cetyl- and stearyl alcohols

Cutina E 24--glycerine monostearate

Cetiol SB 45--shea butter (fatty acid glyceride)

Eutanol G--octyldodecanol

Cutina CBS--mono-, di- and triglycerides, fatty alcohols, wax esters

Labrafil M 1944--apricot kernel oil, polyethylene glycol-6-complex

I claim:
 1. A method for the treatment of infantile seborrheic eczemacomprising administering to a patient suffering from infantileseborrheic eczema a composition comprising at least one essential fattyacid having 18-20 carbon atoms in an amount sufficient for saidtreatment.
 2. A method according to claim 1 wherein said at least oneessential fatty acid having a 18-20 carbon atoms is administered incomposition form and wherein said composition comprises at least 0.1% ofsaid at least one essential fatty acid.
 3. A method according to claim 1wherein said at least one essential fatty acid is administered incomposition form comprising 0.5-50% by weight of said at least oneessential fatty acid having 18-20 carbon atoms, and at least onepharmaceutically acceptable carrier for said fatty acid.
 4. A methodaccording to claim 1 wherein said at least one essential fatty acid isadministered in composition form comprising 1-20% by weight of said atleast one essential fatty acid having 18-20 carbon atoms, and at leastone pharmaceutically acceptable carrier for said fatty acid.
 5. A methodaccording to claim 1 wherein said at least one essential fatty acid isadministered in composition form comprising 5-10% by weight of said atleast one essential fatty acid having 18-20 carbon atoms, and at leastone pharmaceutically acceptable carrier for said fatty acid.
 6. A methodaccording to claim 1 wherein said at least one essential fatty acid isgammalinolenic acid.
 7. A method according to claim 1 wherein saidcomposition consists essentially of a vegetable oil containing said atleast one fatty acid having 18-20 carbon atoms.
 8. A method according toclaim 1 wherein said composition consists essentially of eveningprimrose oil or borage oil.
 9. A method according to claim 1 whereinsaid treatment is by topical application and said composition is anointment or cream.
 10. A method according to claim 1 wherein saidcomposition further comprises 1-30% by weight of zinc based on the totalcomposition, or 0.1-10% by weight of PGE₁ or PGE₂ based on the totalcomposition, or a mixture thereof.
 11. A method according to claim 1wherein said composition further comprises 15-25% by weight of zincbased on the total composition, or 0.1-2% by weight of PGE₁ or PGE₂based on the total composition, or a mixture thereof.
 12. A methodaccording to claim 1 wherein said administration is orally in an amountof 100-600 mg.
 13. A method in accordance with claim 1 wherein saidadministration is intravenous.